US10668126B2 - Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor - Google Patents
Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor Download PDFInfo
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- US10668126B2 US10668126B2 US11/061,932 US6193205A US10668126B2 US 10668126 B2 US10668126 B2 US 10668126B2 US 6193205 A US6193205 A US 6193205A US 10668126 B2 US10668126 B2 US 10668126B2
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Definitions
- the invention relates generally to therapeutic formulations for use in the treatment of neoplasias. More specifically, the invention relates to pharmaceutical formulations comprised of chemotherapeutic agents and biotherapeutic agents for treating neoplasias. Methods for treating neoplasias by administering combinatorial formulations of neoplasia-treating agents, such as chemotherapeutic and/or radiation, along with biotherapeutic agents are also disclosed.
- neoplasia-treating agents such as chemotherapeutic and/or radiation
- Cancer is the second leading cause of death in the United States, surpassed only by heart disease. According to the American Cancer Society, approximately 556,000 Americans die from cancer each year-an average of more than 1,500 cancer deaths each day (Jemal, A. et al., CA Cancer J. Clin., 55, 10-30, 2005). Of the different cancers not including the skin cancers, lung cancer is the leading cause of cancer death for both men and women; breast cancer is the second leading cause of cancer death in women; prostate cancer is the second leading cause of cancer death in men and colorectal cancer is the third most frequently diagnosed form of cancer.
- Pancreatic cancer is the most lethal human cancer with median survival for all stages of pancreatic cancer being less than 3-5 months from diagnosis.
- CA Cancer J. Clin, 2004 54:8-20 The five-year survival rate is 3% or less. In spite of treatment efforts of surgery, radiation, and chemotherapy, the survival rate remains unchanged.
- CA Cancer J. Clin, 2004 The incidence of pancreatic cancer is only 0.01% in the United States, but it is associated with the deaths of over 30,000 individuals each year, making this the most common in terms of cancer mortality. (Jemal, A. et al., CA Cancer J. Clin., 55, 10-30, 2005).
- pancreatic tumors can be removed by surgery.
- a combination of radiotherapy and chemotherapy is usually performed.
- chemotherapy alone is usually used.
- the standard chemotherapy agent is gemcitabine, but other drugs may be used. Gemcitabine essentially provides only palliative improvement in patients.
- Head and neck cancer is the sixth ranking cancer in the world, and the third most common neoplasia in developing nations.
- the incidence of cancer of the aerodigestive tract accounts for approximately 40,000 new cases each year, with over 11,000 fatalities recorded annually (Jemal, A. et al., CA Cancer J. Clin., 55, 10-30, 2005).
- More than 90% of head and neck cancers are squamous cell carcinomas (SCCHN), with the oral cavity and pharynx being the most common sites for SCCHN, followed by the larynx. Surgery, radiotherapy and chemotherapy, and combinations thereof, are all considered for treatment.
- SCCHN squamous cell carcinomas
- EGF epidermal growth factor
- transforming growth factors ⁇ and ⁇ basic fibroblast growth factor
- IGF insulin-like growth factor
- PDGF platelet derived growth factor
- KGF keratinocyte growth factor
- One group of peptides, the endogenous opioids, are believed to be important in the growth of normal, neoplastic, renewing and healing tissues, as well as in prokaryotes and eukaryotes (Zagon, I. S. et al., In: Cytokines: Stress and Immunity. Plotnikoff N P et al., (eds). CRC Press, Boca Raton, Fla., pp. 245-260, 1999).
- Met-enkephalin an endogenous opioid peptide, is directly involved in growth processes, and serves as a negative regulator in a wide variety of cells and tissues (Zagon, I. S. et al., In: Receptors in the Developing Nervous System. Vol. 1.
- OGF opioid growth factor
- chemotherapeutic agents are used for their lethal action to cancer cells. Unfortunately, few such drugs differentiate between a cancer cell and other proliferating cells. Chemotherapy generally requires use of several agents concurrently or in planned sequence. Combining more than one agent in a chemotherapeutic treatment protocol allows for: (1) the largest possible dose of drugs; (2) drugs that work by different mechanisms; (3) drugs having different toxicities; and (4) the reduced development of resistance.
- Chemotherapeutic agents mainly affect cells that are undergoing division or DNA synthesis, thus slow growing malignant cells, such as lung cancer or colorectal cancer, are often unresponsive. Furthermore, most chemotherapeutic agents have a narrow therapeutic index. Common adverse effects of chemotherapy include vomiting, stomatitis, and alopecia. Toxicity of the chemotherapeutic agents is often the result of their effect on rapidly proliferating cells, which are vulnerable to the toxic effects of the agents, such as bone marrow or from cells harbored from detection (immunosuppression), gastrointestinal tract (mucosal ulceration), skin and hair (dermatitis and alopecia).
- cytotoxic agents act at specific phases of the cell cycle (cell cycle dependent) and have activity only against cells in the process of division, thus acting specifically on processes such as DNA synthesis, transcription, or mitotic spindle function.
- Other agents are cell cycle independent. Susceptibility to cytotoxic treatment, therefore, may vary at different stages of the cell life cycle, with only those cells in a specific phase of the cell cycle being killed. Because of this cell cycle specificity, treatment with cytotoxic agents needs to be prolonged or repeated in order to allow cells to enter the sensitive phase.
- Non-cell-cycle-specific agents may act at any stage of the cell cycle; however, the cytotoxic effects are still dependent on cell proliferation. Cytotoxic agents thus kill a fixed fraction of tumor cells, the fraction being proportionate to the dose of the drug treatment.
- neoplasia-treating agents are currently in use today, including any chemotherapeutic agents, and biotherapeutic agents as well as radiation therapy.
- chemotherapeutic agents including alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, mitotic inhibitors, corticosteroid hormones, sex hormones, immunotherapy or others such as L-asparaginase and tretinoin.
- Gemcitabine is a pyrimidine analogue that belongs to a general group of chemotherapy drugs known as antimetabolites and that also acts as a radiation-sensitizing agent. Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis, i.e., the S-phase, and also blocks the progression of cells through the G 1 /S-phase boundary.
- Gemcitabine is an approved chemotherapeutic agent for a wide range of tumors that include, but are not limited to, pancreatic and colorectal carcinoma.
- the efficacy of gemcitabine is marginal, however, and life expectancy is rarely extended, particularly for pancreatic cancer patients.
- Side effects of gemcitabine administration are relatively mild when compared to other chemotherapeutic agents, consisting of myelosuppression with increased risk of infection, decreased platelet count with increased risk of bleeding, nausea, vomiting, increased liver function blood tests and fatigue.
- Gemcitabine in general, however, has replaced other therapies because of its less toxic effects on the patient, and hence, a better quality of life.
- the platin family of chemotherapeutics consists primarily of cisplatin and carboplatin.
- Cisplatin is an inorganic platinum complex that disrupts the DNA helix by forming intra- and interstrand cross-links. Cisplatin also reacts, however, with nucleophils of other tissues, causing toxic effects on the kidney and on the eight cranial nerve (which is responsible for causing intense nausea and vomiting). Other side effects include renal toxicity, ototoxicity manifested by tinnitus and hearing loss, and mild to moderate myelosuppression.
- Carboplatin differs from cisplatin mainly with respect to side effects. Myelosuppression is the dose-limiting toxicity for carboplatin with very little of the renal, neurologic, or ototoxicities that are encountered with cisplatin.
- Paclitaxel is a natural, although quite toxic, substance derived from the yew tree that is chemically altered to produce a powerful anti microtubule chemotherapeutic agent indicated for the treatment of metastatic breast cancer, metastatic ovarian cancer, and Kaposi's sarcoma. Paclitaxel also has been used to treat SCCHN, non-small cell lung cancer, small cell lung cancer and bladder cancer. Side effects commonly encountered with paclitaxel administration include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, pain in the joints of the arms or legs lasting 2-3 days, changes in the color of nails and tingling in hands or toes.
- 5-FU The chemotherapeutic agent, 5 fluorouracil
- 5-FU has been one of the major antimetabolites used in a variety of solid cancers since the 1960s.
- 5-FU prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus disrupting the growth of cancer cells.
- 5-FU is used alone or in combination in the adjuvant treatment of breast, colon, gastrointestinal and head or neck cancer.
- 5-FU also is used as a palliative therapy of inoperable malignant neoplasms, such as of the gastrointestinal tract, breast, liver, genitourinary system and pancreas.
- 5-FU has many common side effects, including myelosuppression with increased risk of infection and bleeding, darkening of skin and nail beds, nausea, vomiting, sores in mouth or on the lips, thinning hair, diarrhea, brittle nails, increased sensitivity to the sun and dry, flaky skin.
- the present invention provides for the first time a carcinotherapeutic pharmaceutical composition and/or treatment method for treating neoplasias in an animal or human comprised of a carrier and therapeutically effective amounts of at least one neoplasia treating agent, such as chemotherapeutic agent or radiation therapy (agent) and the biotherapeutic endogenous pentapeptide Met-enkephalin, referred to as opioid growth factor (OGF).
- a carcinotherapeutic composition refers to a composition that includes both chemotherapeutic and biotherapeutic agents for the treatment of all neoplasias, including but not limited to true carcinomas but also other cancers such as sarcomas, melanomas, etc.
- OGF oxygen styrene-maleic anhydride copolymer
- OGF receptor a similar fashion to OGF as described herein. This also includes synthetic or any other compound which mimics the biological activity of OGF in its interaction with the OGF receptor.
- Met-enkephalin shall be interpreted to include the endogenous pentapeptide Met-enkephalin.
- the present invention also provides a method of treating neoplasias in an animal or human in need of such treatment, comprising the administration to the animal or human therapeutically effective amounts of each of at least one neoplasia-treating agent and OGF.
- neoplasia-treating agents have been shown to be effective when used in combination with OGF including anti-metabolites, cytosine analogs, cross linking agents and the like.
- the effects of OGF are mediated through the OGFr and thus it is postulated that any chemotherapeutic agent, or biotherapeutic agent, will have similar effects, including radiation therapy.
- Neoplasia-treating agents can include any chemotherapeutic agents as well as radiation therapy.
- chemotherapeutic agents include but are not limited to alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, mitotic inhibitors, corticosteroid hormones, sex hormones, immunotherapy or others such as L-asparaginase and tretinoin.
- the combination of the biotherapeutic OGF and neoplasia treating agent is in most cases at least additive which will allow for a reduction in toxicity of the treatment as a similar result may be achieved with a lower dose of the neoplasia treating agent. This is important as many of these agents are highly toxic and should be used in as small dose as possible. In at least one protocol the reduction in toxicity was seen in addition to the additive nature of the agents. Often the result of the combination is a synergistic effect, i.e. the reduction in cells is greater than the sum of each of the agents alone. The effects of the OGF are blocked by naloxone indicating that the OGF effect is entirely mediated by the OGFr.
- the OGFr may be introduced to tumor cells in a suicide type treatment protocol where tumor or neoplasia cells will be sensitized to the anti-neoplastic treatment by the introduction of additional OGFr receptors to the cells so that OGF may interact with as many cells as possible in mediating and potentiating the effect of the therapy.
- Neoplasias that can be treated according to the method of the present invention include any neoplasia cell that has an OGFr, this can include without limitation, pancreatic cancer, squamous cell cancer of the head and neck, breast cancer, colorectal cancer, renal cancer, brain cancer, prostate cancer, bladder cancer, bone or joint cancer, uterine cancer, cervical cancer, endometrial cancer, multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma, melanoma, leukemias, lung cancer, ovarian cancer, gastrointestinal cancer, Kaposi's sarcoma, liver cancer, pharyngeal cancer or laryngeal cancer.
- the effective therapeutic amount of OGF that can be administered according to the composition in an intravenous protocol for example between about 20 to 1000 ⁇ g/kg body weight per day, preferably about 100 to 400 ⁇ g/kg body weight.
- OGF may be administered at least once a week, and as frequently as multiple times daily, throughout the entire treatment period depending on the route of administration.
- OGF is non-toxic and may be administered in accordance with essentially any effective dose.
- the mode of administration, i.e. intravenous, subcutaneous, etc. may also alter the effective dose and timetable of drug administration, but such can be determined through routine experimentation.
- the antineoplastic agent may be administered sequentially, or simultaneously with the administration of OGF, at least one neoplasia treating agent is administered to an animal or human in therapeutically effective amounts of, for example, between about 20 to 3000 mg/m 2 , preferably about 100 to 1000 mg/m 2 , over a period of between about 10 to 60 minutes, and preferably about 30 minutes, at least once a week for about three to ten weeks, preferably seven weeks.
- the chemotherapeutic agent is administered over a period of between about 10 to 60 minutes, preferably about 30 minutes, for about one to five weeks, preferably three weeks.
- Administration of the chemotherapeutic agent can repeat every two to eight weeks, preferably four weeks, in the absence of disease progression or unacceptable toxicity. Subcutaneous or implant delivery will also be effective.
- OGF is administered in an effective dose of about 20 to 1000 ⁇ g/kg body weight, preferably about 100 to 400 ⁇ g/kg body weight at least three times a week, preferably daily, during the course of radiation therapy.
- OGF is administered in an effective dose of about 20 to 1000 ⁇ g/kg body weight, preferably about 100 to 400 ⁇ g/kg body weight at least three times a week, preferably daily, with chemotherapy during the course of radiation therapy.
- the route of administration of the antineoplastic agent(s) and opioid growth factor includes, without limitation, parenteral administration, namely intravenous, intramuscular or intraperitoneal, subcutaneous, implanted osmotic pump or transdermal patch.
- FIG. 1 is a graph representing a 96-hour growth curve for SCC-1 cells being treated with paclitaxel (Taxol) and/or OGF. Each data point represents the average absorbency for 10 wells ⁇ S.E.M. Significance values for each timepoint can be found on Table 1.
- FIG. 2 is a graph representing a 96-hour growth curve for SCC-1 cells being supplemented with carboplatin and/or OGF. Each data point represents the average absorbency for 10 wells ⁇ S.E.M. Significance values for each timepoint can be found on Table 2.
- FIG. 3 shows the growth of SCC-1 SCCHN cells in athymic nude mice.
- Timepoint 1 signifies the first day that tumors became measurable in each treatment group. Tumor volumes were recorded every day and averages from 2 consecutive days represent the timepoints on the x-axis.
- FIG. 4 shows the final termination weights for athymic nude mice inoculated with SCC-1 SCCHN cells. Bars represent the mean values for weight for the entire treatment group at the time of termination (Day 50). Significant from controls at p ⁇ 001 (***), significant from OGF at p ⁇ 0.001 (+++), and significant from Taxol/OGF at p ⁇ 0.001 ( ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ ).
- FIG. 5 shows a survival curve representing the percent of surviving mice in each of the four groups over the course of the 50-day study.
- FIG. 6 is a graph representing a 96-hour growth curve for MiaPaCa-2 cells treated with gemcitabine and/or OGF. Each data point represents the average absorbency for 10 wells ⁇ S.E.M. Significance values for each timepoint can be found on Table 3.
- FIG. 7 is a graph representing a 96-hour growth curve for MiaPaCa-2 cells being treated with 5-FU and/or OGF. Each data point represents the average absorbency for 10 wells ⁇ S.E.M. Significance values for each timepoint can be found on Table 4.
- FIG. 8 shows the growth of MiaPaCa-2 human pancreatic cancer cells in athymic nude mice.
- Timepoint 1 signifies the first day that tumors became measurable in each treatment group. Tumor volumes were recorded every day and averages from 2 consecutive days represent the timepoints on the x-axis. Graph is meant to show growth trends once tumors became measurable in each group. Graph disregards latency to measurable tumor development to illustrate this trend.
- FIG. 9 shows the growth of MiaPaCa-2 human pancreatic cancer cells against time subjected to daily addition of the above drug regiments. Values represent the means from 4 wells/timepoint ⁇ S.E.M. Significance values can be found on Table 5.
- FIG. 10 shows cell proliferation assays of MIA PaCa-2 cells subjected to OGF (10 ⁇ 6 M) and/or gemcitabine (10 ⁇ 8 ) (Gemzar) for 96 hr.
- Drugs or an equivalent volume of sterile water (controls) were added 24 hr (0 hr) after seeding in 6-well plates; media and drugs were replaced daily.
- Data represent means ⁇ SEM for at least 4 wells per treatment at each time point.
- Significantly different from cultures treated with gemcitabine alone at p ⁇ 0.001 ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ ).
- FIG. 11 depicts receptor mediation of the growth inhibitory effects of gemcitabine and/or OGF in MIA PaCa-2 cells.
- the number of MIA PaCa-2 cells at 96 hr as measured by the MTS assay after being subjected to OGF (10 ⁇ 6 M), the opioid antagonist naloxone (10 ⁇ 6 M), gemcitabine (Gemzar) (10 ⁇ 8 M), or combinations of these compounds; controls were treated with an equivalent volume of sterile water. Compounds and media were replaced every 24 hr. Data represent mean absorbency ⁇ SEM for 10 wells/treatment at 96 hr. Significantly from controls at p ⁇ 0.001 (***). NS not significant.
- FIG. 12 shows reversibility of the growth inhibitory effects on MIA PaCa-2 cells treated with OGF and/or gemcitabine (Gemzar).
- Cells were seeded into 96-well plates and treated with drugs for 48 hr. At 48 hr, half of the plates continued to receive the same drugs for an additional 48 hr, and half of the plates were treated with sterile water for 48 hr. Control cultures received sterile water throughout the 96 hr. Compounds and media were replaced daily.
- A Growth of cells in the reversibility experiments.
- FIG. 13 shows growth of MIA PaCa-2 cells grown in 96-well plates treated with a variety of endogenous and exogenous opioids at a concentration of 10 ⁇ 6 M. Data represent mean absorbency values ⁇ SEM for 10 wells/treatment. Significantly different from controls at p ⁇ 0.001 (***).
- FIG. 14 shows effects of gemcitabine (10 ⁇ 8 M) (Gemzar) and/or OGF (10 ⁇ 6 M) on PANC-1 cells grown in 6-well plates. Data represent means ⁇ SEM for 4 well at 72 hr of treatment. Significantly different from controls at p ⁇ 0.001 (***), from OGF at p ⁇ 0.01 (++), and from the respective dosages of gemcitabine at p ⁇ 0.001 ( ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ ).
- FIG. 15 shows growth of MIA PaCa-2 tumors xenografted into nude mice.
- Animals were injected with either 10 mg/kg OGF daily, 120 mg/kg gemcitabine every 3 days (Gemzar); 10 mg/kg OGF daily and 120 mg/kg gemcitabine every 3rd day (Gemzar/OGF), or 0.1 ml of sterile saline daily (Control).
- A. Tumor volumes monitored for the 45 days of the experiment. Values represent means ⁇ SEM for all mice in the group (see Results for statistical comparisons).
- B Rates of tumor growth for the 45-day experimental period. Tumor volumes were log-transformed and slopes of the lines were calculated.
- FIG. 16 depicts growth of MIA PaCa-2 cells treated with 5-FU (10 ⁇ 6 M) and/or OGF (10 ⁇ 6 M) as measured by the MTS assay (96-well plates). Values represent mean absorbencies ⁇ SEM for 10 wells at each time point. Significantly different from controls at p ⁇ 0.05 (*), p ⁇ 0.01 (**), and p ⁇ 0.001 (***). Significantly different from OGF-treated cultures at p ⁇ 0.001 (+++). Significantly different from 5-FU-treated cultures at p ⁇ 0.01 ( ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ ) and p ⁇ 0.001 ( ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ ).
- A. Growth curve data represent means ⁇ SE for at least 4 wells/treatment at each time point. Significantly different from controls at p ⁇ 0.05 (*), p ⁇ 0.01 (**), and p ⁇ 0.001 (***). Significantly different from OGF-treated cultures at p ⁇ 0.01 (++) and p ⁇ 0.001 (+++).
- FIG. 18 depicts growth of SCC-1 cells treated with carboplatin and/or OGF as measured by the MTS assay. Values represent mean absorbencies ⁇ SE for 10 wells at each time point. Significantly different from controls at p ⁇ 0.001 (***). Significantly different from OGF-treated cultures at p ⁇ 0.001 (+++). Significantly different from carboplatin-treated cultures at p ⁇ 0.001 ( ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ ).
- FIG. 19 shows OGFr mediation of the growth inhibitory effects of paclitaxel and/or OGF in SCC-1 cells.
- the number of SCC-1 cells at 96 hr as measured by the MTS assay after being subjected to OGF (10 ⁇ 6 M), the opioid antagonist naloxone (10 ⁇ 6 M), paclitaxel (Taxol) (10 ⁇ 8 M), or combinations of these compounds; controls were treated with an equivalent volume of sterile water. Compounds and media were replaced every 24 hr. Data represent mean absorbency ⁇ SE for 10 wells/treatment. Significantly different from controls at p ⁇ 0.001 (***). NS not significant.
- FIG. 20 shows the reversibility of the growth inhibitory effects on SCC-1 cells treated with OGF and/or paclitaxel (Taxol).
- Cells were seeded into 96-well plates and treated with drugs for 48 hr. At 48 hr, half of the plates continued to receive the same drugs for an additional 48 hr, and half of the plates were treated with sterile water for 48 hr. Control cultures received sterile water throughout the 96 hr. Compounds and media were replaced daily.
- FIG. 21 depicts the growth of SCC-1 cells treated with a variety of endogenous and exogenous opioids. Data represent mean absorbency values ⁇ SE for 10 wells/treatment. Significantly different from controls at p ⁇ 0.001 (***).
- FIG. 22 shows the evaluation of apoptosis in SCC-1 cells treated with OGF and/or paclitaxel for 24, 72, to 144 hours.
- Cells were seeded into 6-well plates, treated with drugs and, at appropriate times, stained with caspase-3. Caspase-3 activity was measured by flow cytometry on 10,000 cells/treatment/time. Data represent the percent caspase positive cells (mean ⁇ SE) for 3 samples for each treatment at each time point. Significantly different from controls at p ⁇ 0.001 (***) and from OGF at p ⁇ 0.001 (+++). Cells exposed to the combined therapy also differed from paclitaxel treated cells at p ⁇ 0.001 ( ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ ).
- FIG. 23 shows the evaluation of DNA synthesis by monitoring BrdU incorporation in SCC-1 cells treated with OGF and/or paclitaxel for 24 hr or 72 hr.
- Data represent the percent BrdU positive cells (mean ⁇ SE) from analysis of at least 1000 cells for each treatment at each time point.
- FIG. 24 shows the effects of paclitaxel and/or OGF on CAL-27 cells, a poorly-differentiated SCCHN cell line. Data represent means ⁇ SEM for 4 samples at 48 hr of treatment. Significantly different from controls at p ⁇ 0.001 (***), from OGF at p ⁇ 0.001 (+++), and from the respective dosages of paclitaxel at p ⁇ 0.01 ( ⁇ circumflex over ( ) ⁇ circumflex over ( ) ⁇ ).
- FIG. 25 shows changes in tumor volume over the 50 days of the experiment analyzed using a non-linear mixed effects model for clustered data. These analyses were performed to accommodate the marked loss of paclitaxel mice beginning on day 20. Tumor volumes of mice in all 3 treatment groups were significantly (p ⁇ 0.001) smaller than controls. Moreover, tumor volumes for mice receiving combined therapy were significantly (p ⁇ 0.001) smaller than tumor sizes in groups receiving either treatment alone. Animals were given intraperitoneal injections of either sterile saline (0.1 ml; Control) daily, OGF (10 mg/kg) daily, paclitaxel (8 mg/kg; Taxol) every other day, or paclitaxel every other day and OGF daily (Taxol/OGF).
- FIG. 26 shows body weights of mice treated with either OGF (10 mg/kg, daily) and/or paclitaxel (8 mg/kg every 2 days; Taxol); control animals received 0.1 ml sterile saline (Control). Body weights were recorded every 7 days; values represent means ⁇ SEM. No significant differences in body weights between Control, OGF, or Taxol groups were recorded.
- FIG. 27 shows the survival curves of mice inoculated with 2 ⁇ 10 6 SCC-1 squamous cells of the head and neck and treated with either OGF (10 mg/kg, daily) and/or paclitaxel (8 mg/kg every 2 days; Taxol); control animals received 0.1 ml sterile saline (Control). Kaplan-Meier curves were analyzed and the survival of mice receiving only paclitaxel was significantly different from all other groups at p ⁇ 0.001.
- the present invention provides for the first time a carcinotherapeutic pharmaceutical composition and method for treating neoplasias in an animal or human comprised of a carrier and therapeutically effective amounts of at least one chemotherapeutic agent and the biotherapeutic endogenous pentapeptide Met-enkephalin, referred to as opioid growth factor (OGF).
- OGF opioid growth factor
- Neoplasia-treating agents can include any biotherapeutic agents, radiopharmaceuticals, and chemotherapeutic agents as well as radiation therapy.
- chemotherapeutic agents any of which may be used according to the invention. These include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, mitotic inhibitors, corticosteroid hormones, sex hormones, immunotherapy or others such as L-asparaginase and tretinoin.
- examples of biotherapeutic agents include but are not limited to interferon, interleukin, tumor derived activated cells. Radionuclides such as Iodine 125 , are also pertinent as well as radiation therapy from gamma or x-rays.
- Chemotherapeutic alkylating agents work directly on DNA to prevent the cancer cell from reproducing. As a class of drugs, these agents are not phase-specific (in other words, they work in all phases of the cell cycle). These drugs are active against chronic leukemias, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, and certain cancers of the lung, breast, and ovary.
- alkylating agents include busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine (DTIC), mechlorethamine (nitrogen mustard), and melphalan.
- Nitrosoureas act in a similar way to alkylating agents. They interfere with enzymes that help repair DNA. These agents are able to travel to the brain so they are used to treat brain tumors as well as non-Hodgkin's lymphomas, multiple myeloma, and malignant melanoma. Examples of nitrosoureas include carmustine (BCNU) and lomustine (CCNU).
- BCNU carmustine
- CCNU lomustine
- Antimetabolites are a class of drugs that interfere with DNA and RNA growth. These agents work during the S phase and are used to treat chronic leukemias as well as tumors of the breast, ovary, and the gastrointestinal tract. Examples of antimetabolites include 5-fluorouracil, capecitabine, methotrexate, gemcitabine, cytarabine (ara-C), and fludarabine.
- Antitumor antibiotics interfere with DNA by stopping enzymes and mitosis or altering the membranes that surround cells. (They are not the same as antibiotics used to treat infections.) These agents work in all phases of the cell cycle. Thus, they are widely used for a variety of cancers. Examples of antitumor antibiotics include dactinomycin, daunorubicin, doxorubicin (Adriamycin), idarubicin, and mitoxantrone.
- Mitotic inhibitors are plant alkaloids and other compounds derived from natural products. They can inhibit, or stop, mitosis or inhibit enzymes for making proteins needed for reproduction of the cell. These work during the M phase of the cell cycle. Examples of mitotic inhibitors include paclitaxel, docetaxel, etoposide (VP-16), vinblastine, vincristine, and vinorelbine.
- Steroids are natural hormones and hormone-like drugs that are useful in treating some types of cancer (lymphoma, leukemias, and multiple myeloma) as well as other illnesses. When these drugs are used to kill cancer cells or slow their growth, they are considered chemotherapy drugs. They are often combined with other types of chemotherapy drugs to increase their effectiveness. Examples include prednisone and dexamethasone.
- Sex hormones or hormone-like drugs, alter the action or production of female or male hormones. They are used to slow the growth of breast, prostate, and endometrial (lining of the uterus) cancers, which normally grow in response to hormone levels in the body. These hormones do not work in the same ways as standard chemotherapy drugs. Examples include anti-estrogens (tamoxifen, fulvestrant), aromatase inhibitors (anastrozole, letrozole), progestins (megestrol acetate), anti-androgens (bicalutamide, flutamide), and LHRH agonists (leuprolide, goserelin).
- Some drugs are given to people with cancer to stimulate their immune systems to more effectively recognize and attack cancer cells. These drugs offer a unique method of treatment, and are often considered to be separate from “chemotherapy.”
- Some chemotherapy drugs act in slightly different ways and do not fit into any of the other categories. Examples include such drugs as L-asparaginase and tretinoin.
- the combination therapy has been exemplified herein with the alkylating agent, carboplatin, the antimetabolite 5-FU, and gemcitabine, and a mitotic inhibitor Paclitaxel.
- Neoplasias that can be treated according to the method of the present invention include, without limitation, pancreatic cancer, squamous cell cancer of the head and neck, breast cancer, colorectal cancer, renal cancer, brain cancer, prostate cancer, bladder cancer, bone or joint cancer, uterine cancer, cervical cancer, endometrial cancer, multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma, melanoma, leukemias, lung cancer, ovarian cancer, gastrointestinal cancer, Kaposi's sarcoma, liver cancer, pharyngeal cancer or laryngeal cancer.
- the effective therapeutic amount of OGF that can be administered according to the composition and method of the present invention for an intravenous therapy is between about 20 to 1000 ⁇ g/kg body weight per day, preferably about 100 to 400 ⁇ g/kg body weight per day.
- OGF may be administered at least three times a week, and as frequently as once daily, throughout the entire treatment period.
- OGF is safe and nontoxic and may be administered in essentially any amount necessary to be effective.
- the route of administration (intravenous, subcutaneous, etc) may affect the amounts than can be given however this is all determined thorough routine experimentation.
- At least one chemotherapeutic agent is administered to an animal or human in therapeutically effective amounts of between about 20 to 3000 mg/m 2 , preferably about 100 to 1000 mg/m 2 , over a period of between about 10 to 60 minutes, and preferably about 30 minutes, at least once a week for about three to ten weeks, preferably seven weeks.
- the chemotherapeutic agent is administered over a period of between about 10-60 minutes, preferably about 30 minutes, for about one to five weeks, preferably three weeks.
- Administration of the chemotherapeutic agent can repeat every two to eight weeks, preferably four weeks, in the absence of disease progression or unacceptable toxicity.
- OGF is administered in an effective dose of about 20 to 1000 ⁇ g/kg body weight, preferably about 100 to 400 ⁇ g/kg body weight at least three times a week, preferably daily, during the course of radiation therapy.
- the route of administration of the chemotherapeutic agent(s) and opioid growth factor include, without limitation, parenteral administration, namely intravenous, intramuscular or intraperitoneal, subcutaneous, implanted slow release osmotic minipump or transdermal patch.
- the OGF pentapeptide is a constitutively expressed autocrine inhibitory growth factor in a wide variety of cells and tissues both in vivo and in vitro, and under normal (e.g., homeostatic development) and abnormal (e.g., cancer, wound healing) conditions.
- the action of OGF in vitro is stereospecific, reversible, non-cytotoxic, independent of serum and occurs at physiologically relevant concentrations.
- the combination of OGF and gemcitabine reduced cell number from control levels by 26% to 46% within 48 hr, and resulted in a growth inhibition greater than that of the individual compounds.
- the combination of OGF and gemcitabine also repressed the growth of a second pancreatic cancer cell line.
- addition of OGF to gemcitabine therapy in nude mice reduces tumor volume more than either compound alone. Tumor weight and tumor volume were reduced from control levels by 36% to 85% in the OGF and/or gemcitabine groups on day 45 and the group of mice exposed to a combination of OGF and gemcitabine had decreases in tumor size of 62% to 77% from the OGF or the gemcitabine alone groups.
- OGF in combination with 5-fluorouracil also depressed cell growth more than either agent alone in a pancreatic cancer cell line.
- Carboplatin also resulted in an additive effect reducing squamous cancer cell number by 14-27%.
- OGF may confer protective effects against the cytotoxicity encountered with some chemotherapeutic agents, such as paclitaxel.
- OGF and the OGFr have been detected in epithelium of rodent and human tongue, skin, gastrointestinal tract, and cornea. It has been shown that both OGF and the OGFr are present in human tumors when obtained at the time of surgical resection. Additionally, DNA synthesis of epithelial cells in mammalian tongue, epidermis, cornea and esophagus has been shown to be regulated by OGF, and does so in a receptor-mediated fashion.
- OGF has been found to be associated with a reduction in cell number, suggesting that a target of OGF is cell replication.
- the cell cycle is composed of five phases: the presynthetic or G 1 phase; synthesis of DNA or S phase; post synthetic or G 2 phase (this phase contains double complement of DNA dividing into two daughter G 1 cells); and mitosis or M phase. Newly divided cells may reenter the cycle or go into a resting or G 0 phase.
- OGF has been shown to alter the proportion of cells in phases of the cell cycle so that within about two hours there is a marked increase in the number of cells in G 0 /G 1 and a compensatory decrease in cells in the S and G 2 /M phases. Moreover, OGF appears to increase dramatically the length of the G 0 /G 1 phase, thus accounting for the notable increase in doubling time of the total cell cycle that is observed.
- Gemcitabine is a pyrimidine analogue that belongs to a general group of chemotherapy drugs known as antimetabolites that also acts as a radiation-sensitizing agent. Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis, i.e., the S-phase, and also blocks the progression of cells through the G 1 /S-phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis.
- dFdCDP active gemcitabine diphosphate
- dFdCTP triphosphate
- gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the concentrations of deoxynucleotide, including dCTP.
- gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentrations of dCTP (by the action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands.
- DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strands (masked chain termination).
- gemcitabine induces internucleosomal DNA fragmentation, one of the characteristics of programmed cell death.
- Paclitaxel also known as Taxol, is derived from the bark and leaves of the Pacific yew (another source is from the needles of a European yew). Paclitaxel is very lipid soluble and must be administered intravenously soon after preparation. Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
- Paclitaxel side effects include transient bradycardia, peripheral neuropathy, nausea, vomiting, diarrhea, neutropenia, thrombocytosis, bronchospasm, urticaria, angioedema, alopecia and myalgias.
- Premedication with dexamethasone, diphenhydramine, and H2 antagonists are used to reduce hyposensitivity reactions.
- Carboplatin and cisplatin belong to the platin family of chemotherapeutic agents, inorganic platinum complexes that disrupt the DNA helix by forming intra- and interstrand cross-links. Cisplatin in particular reacts with nucleophils of other tissues, hence its toxic effect on the kidney, the eight cranial nerve, and the intense emesis.
- carboplatin and cisplatin are concentrated in the kidney, liver, intestines and testes, but they do not cross the blood brain barrier. They are usually used with other agents in metastatic testicular, ovarian carcinoma, and advanced bladder cancer. Side effects are commonly encountered with cisplatin administration, and include renal toxicity, ototoxicity manifested by tinnitus and hearing loss, marked nausea and vomiting. Additionally, mild to moderate myelosuppression may develop. Carboplatin differs from cisplatin mainly in side effects, as myelosuppression is the dose-limiting toxicity for carboplatin with very little of renal, neurologic, or ototoxicity.
- 5-FU as a single agent has an activity superior to that of any other single agent in the treatment of carcinomas of the colon and rectum. It is used primarily for slowly growing solid tumors, such as carcinomas of the breast and the gastrointestinal tract. The mean response rate is still low, however, being less than 20%. Inactive as such, fluorouracil must be converted to the 5′-monophosphate nucleotide where it may inactivate enzymes essential to synthesize thymidylate, or where it acts within a complex pathway. 5-FU is incorporated into RNA and inhibits DNA synthesis. 5-FU is converted into the active 5-fluoro-deoxyuridine monophosphate (FdUMP) by a variety of different metabolic pathways.
- FdUMP active 5-fluoro-deoxyuridine monophosphate
- the drug acts by inhibiting the enzyme thymidylate kinase which results in reduced formation of thymidine and thus of DNA.
- Fluorouracil, as FdUMP, is also incorporated into RNA, which results in fluoridation of the RNA.
- 5-FU The effect of 5-FU on living cells is limited mainly to those in the proliferative phase. However, while cells in the G 2 and S phases are most affected there may be effects at any stage of the cell cycle. 5-FU is metabolized primarily in the liver, with only 10% of the drug appearing unchanged in urine. 5-FU can enter cerebrospinal fluid. Resistance to 5-FU develops because the cells lose their ability to convert 5-FU to its active form. Common side effects are often delayed. Stomatitis that ulcerates is an early sign of toxicity, and myelosuppression (leukopenia) usually occurs between nine and fourteen days of therapy. Other side effects include alopecia, dermatitis, and atrophy of the skin.
- the carcinotherapeutic composition of the present invention i.e., combining at least one chemotherapeutic agent with the biotherapeutic agent, OGF
- OGF the biotherapeutic agent
- the carcinotherapeutic composition of the present invention exerts its potent inhibitory effect on cancer cell growth by the ability of OGF to accumulate cells in the G 0 /G 1 phase, where the cells are vulnerable to the cytotoxic effects of a chemotherapeutic agent, thus greatly enhancing the number of cells killed by the chemotherapeutic agent.
- a lowered effective dose of the chemotherapeutic agent is needed, therefore, to produce a significantly greater growth inhibition than what would occur without the presence of OGF.
- the growth of cells as represented by absorbency taken at 450 nm from the cell proliferation assay plotted against time was the standard format for presenting the effects of different drugs on SCC-1 or MiaPaCa-2 cells. Cells were counted using a standard MTT assay. In general, each data point represents the average absorbency taken from 10 wells/treatment; error bars represent the S.E.M.
- results illustrated in FIG. 1 and Table I examine the addition of paclitaxel (Taxol) and/or OGF to SCC-1 cells.
- OGF 10 ⁇ 6 M
- Paclitaxel at a concentration of 10 ⁇ 7 M inhibited cell growth at 24, 48, 72, and 96 hours decreasing cell number from controls by 14.2, 34.4, 58, and 70%, respectively.
- Paclitaxel at a concentration of 10-8 also inhibited growth at 72 and 96 hours with decreases in cell number relative to controls of 14.1 and 19.3%, respectively.
- OGF in combination with paclitaxel 10 ⁇ 7 M was significantly more inhibitory than any drug alone at all timepoints (besides paclitaxel 10 ⁇ 7 M at 24 hours) with decreases in cell number ranging from 10.1-75.3%.
- OGF in combination with paclitaxel 10 ⁇ 8 M was significantly more inhibitory than any drug alone at 48, 72, and 96 hours with decreases in cell number ranging from 10.4-27.1%.
- the results illustrated in FIG. 2 and Table 2 examine the addition of carboplatin and/or OGF to SCC-1 cells.
- OGF 10 ⁇ 6 M
- Carboplatin at a concentration of 10 ⁇ 6 M inhibited cell growth at 48, 72, and 96 hours decreasing cell number relative to controls by 5.3, 21.8, and 24.9%, respectively.
- Carboplatin at a concentration 10 ⁇ 7 M also inhibited growth at 72 and 96 hours decreasing cell number relative to controls by 18.7 and 21%, respectively.
- OGF in combination with carboplatin 10 ⁇ 7 M was significantly more inhibitory than OGF alone at 48, 72, and 96 hours, carboplatin 10 ⁇ 6 M at 48 and 72 hours, and carboplatin 10 ⁇ 7 at 48 and 72 hours with decreases in cell number ranging from 10.4-27.1% (Table 2).
- mice At the beginning of the trial, all mice weighed approximately 22-24 grams and mice gained roughly 2 to 4 grams every 5 days. However, by day 20 of the experiment, paclitaxel mice began to lose weight, weighing 11% less than controls (p ⁇ 0.05). Continued weight loss was observed within the paclitaxel group until termination day or the death of the mice (see survival curve FIG. 5 ), on day 50 mice weighed 28% less (p ⁇ 0.001) than controls, OGF, and paclitaxel/OGF treated mice (see FIG. 4 ).
- mice in the paclitaxel group began dying on day 19 (see FIG. 5 ). By day 40, 75% of the paclitaxel treated mice had died and no mouse in any other treatment group, including the paclitaxel/OGF group had perished. On termination day, only one mouse (8% of the group) was still alive. The average life span of the paclitaxel mice was 34.3 ⁇ 3.1 days and this was significantly (p ⁇ 0.001) different from all other treatment groups. One mouse in the paclitaxel/OGF group died on day 40 but all remaining mice were still alive until termination day.
- mice that were injected with SCC-1 cells developed tumors. On day 13 after tumor cell inoculation, 75% of mice, 66% of paclitaxel treated mice, and 58% of paclitaxel/OGF treated mice had tumors.
- control mice When examining latency to a visible tumor, control mice developed visible, but not measurable tumors within 7 days of tumor cell inoculation.
- Paclitaxel and paclitaxel/OGF mice also developed visible tumors within the same 1-week time frame while OGF mice developed tumors within 11 days, exhibiting an approximate 4-day delay in visible tumor development (p ⁇ 0.05).
- the latency time for measurable (62.5 mm 3 ) tumors displayed an analogous pattern to the latency for visible tumors where control, paclitaxel, and paclitaxel/OGF groups had measurable tumors within 2 weeks of tumor cell inoculation while the OGF group developed measurable tumors within 17 days, although this difference was not significant from control values.
- Tumor dimensions were recorded every day beginning on the day that the tumors were considered measurable. These were plotted for every 2 consecutive days of measurements beginning on the first day that each mouse had a measurable tumor over the course of 36 days ( FIG. 3 ).
- both OHGF and paclitaxel/OGF mice had significantly (p ⁇ 0.05) smaller tumors than control mice with reductions of 26% and 29%, respectively.
- all 3 treatment groups had mean tumor volumes that were significantly smaller than controls by 29 to 33%.
- paclitaxel/OGF mice had tumors that were significantly smaller than tumor sizes in groups receiving single treatments. From timepoint 11 (see FIG.
- paclitaxel/OGF mice exhibited tumor volumes that were significantly smaller than both the control and OGF mice, but comparisons to paclitaxel mice revealed no significance due to the fact that mice in the paclitaxel group began to die around this timepoint. Death of the paclitaxel mice made the statistical analysis difficult. In some cases the mice began to exhibit common side effects of the chemotherapy and tumor sizes often decreased. Therefore tumor measurements comparing the paclitaxel and paclitaxel/OGF mice were often non-significant, both due to the decreased tumor size before death and lowered N value in the paclitaxel group.
- the results illustrated in FIG. 7 examine the addition of 5-FU and/or OGF to MiaPaCa-2 cells.
- OGF 10 ⁇ 6 M
- 5-FU at a concentration of 10-5 M inhibited cell growth at 48, 72, and 96 hours decreasing cell number by 26.0, 30.1, and 36.4%, respectively relative to controls.
- 5-FU at a concentration of 10 ⁇ 6 M also inhibited growth at 48, 72 and 96 hours decreasing cell number relative to controls by 12.7, 10.8 and 15.2%, respectively.
- G 1 recruitment remained strong with 73.50% and 60.75% of cells respectively still in G 1 with the gemcitabine/OGF treatment at 48 and 120 hours, 74.03% and 60.15% of cells were arrested in the G 1 phase of the cell cycle.
- mice that were injected with MiaPaCa-2 cells developed tumors.
- all mice in the control saline treatment group as well as the OGF group had a tumor, while 75% of gemcitabine treated mice, and 0% of gemcitabine/OGF (p ⁇ 0.0001) treated mice, had tumors (See FIG. 8 ).
- control mice developed visible, but not measurable, tumors within 10 days of tumor cell inoculation.
- OGF mice and gemcitabine mice also developed tumors within the same 10-day time frame while gemcitabine/OGF mice developed tumors within 16 days, exhibiting an approximate 6-day delay in visible tumor development (p ⁇ 0.05).
- the latency time for measurable (62.5 mm 3 ) tumors displayed an analogous pattern to the latency for visible tumors.
- Control, OGF, and gemcitabine groups had measurable tumors within 2 weeks of tumor cell inoculation while the gemcitabine/OGF group developed measurable tumors within 20 days (p ⁇ 0.05).
- Tumor dimensions were recorded every day beginning on the day that the tumors were considered measurable and data were plotted for every 2 consecutive days of measurements beginning on the first day that each mouse had a measurable tumor over the course of 31 days.
- OGF mice had significantly (p ⁇ 0.01 timepoints 7, 9, and 16, p ⁇ 0.001 timepoint 8, and p ⁇ 0.05 all remaining) smaller tumors than control mice with reductions of 29.9-40.7%, respectively.
- all 3 treatment groups had tumors that were significantly smaller than control tumors.
- gemcitabine/OGF mice had tumors that were significantly smaller than tumor sizes in the OGF group.
- gemcitabine/OGF mice had significantly smaller tumors than the gemcitabine mice alone. Tumor volumes of mice receiving gemcitabine only significantly differed from the tumor volumes of mice receiving OGF at timepoints 4, 5, and 6. Although ANOVA did not reveal many significances between gemcitabine versus gemcitabine/OGF other than mentioned above, volumes of gemcitabine/OGF tumors were smaller by 29.8-56.9% at points that were not deemed significant by ANOVA.
- FIG. 9 illustrates that OGF (10 ⁇ 6 M) alone inhibited growth at 48, 72, and 96 hours with decreases in cell number from controls of 15.5, 17.6, and 16.7%, respectively.
- Gemcitabine at a concentration of 10 ⁇ 7 M inhibited cell growth at 24, 48, 72, and 96 hours decreasing cell number relative to controls by 30.1, 46.4, 47.7, and 64.2%, respectively.
- Gemcitabine at a concentration of 10 ⁇ 8 M also inhibited growth at 48, 72, and 96 hours decreasing cell number relative to controls by 21.7, 21.2, and 32.4%, respectively.
- gemcitabine (10 ⁇ 8 M) When gemcitabine (10 ⁇ 8 M) was combined with OGF (10 ⁇ 6 M), growth inhibition was observed at 48, 72, and 96 hours resulting in decreases in cell number of 26.3, 49.2, and 45.9%, respectively.
- Gemcitabine (10 ⁇ 8 M) when combined with OGF (10 ⁇ 6 M) was significantly more inhibitory than OGF alone at 72 and 96 hours and gemcitabine (10 ⁇ 8 M) alone at 72 and 96 hours (See Table 5).
- Table 1 shows significance values obtained from a one-way ANOVA for paclitaxel and/or OGF versus controls (A), OGF (B), paclitaxel 10 ⁇ 7 M (C), and paclitaxel 10 ⁇ 8 M (D) over a 96-hour trial.
- Table 2 shows significance values obtained from a one-way ANOVA for carboplatin (Carb) and/or OGF versus controls (A), OGF (B), carboplatin 10 ⁇ 6 M (C), and carboplatin 10 ⁇ 7 M (D) over a 96-hour trial.
- Table 3 shows significance values obtained from a one-way ANOVA for gemcitabine and/or OGF versus controls (A), OGF 10 ⁇ 6 M (B), gemcitabine 10 ⁇ 7 M (C), and gemcitabine 10 ⁇ 8 M (D) over a 96-hour trial.
- Table 4 shows significance values obtained from a one-way ANOVA for 5-FU and/or OGF versus controls (A), OGF (B), 5-FU 10 ⁇ 5 M (C), or 5-FU 10 ⁇ 6 M (D) over a 96-hour trial.
- Table 5 shows significance values obtained from a one-way ANOVA for gemcitabine and/or OGF versus controls (A), OGF (B), gemcitabine 10 ⁇ 7 M (C), and gemcitabine 10 ⁇ 8 M (D) over a 96-hour trial.
- the present report addresses the question of whether a combination of OGF and gemcitabine influences growth of human pancreatic cancer in vivo, and does so beyond the efficacy of each compound.
- MIA PaCa-2 and PANC-1 human pancreatic adenocarcinoma cell lines were purchased from the American Type Culture Collection (Manasass, Va.).
- MIA PaCa-2 cells were derived from an undifferentiated epithelial carcinoma occurring in the body and tail of the pancreas in a 65-year-old man [36].
- the PANC-1 cells were derived from an undifferentiated carcinoma from the head of the pancreas in a 56-yr old man [18].
- MIA PaCa-2 and PANC-1 cells were grown in Dulbecco's MEM (modified) media; media was supplemented with 10% fetal calf serum, 1.2% sodium bicarbonate, and antibiotics (5,000 Units/ml penicillin, 5 mg/ml streptomycin, 10 mg/ml neomycin), and the cells were maintained in a humidified atmosphere of 7% CO 2 /93% air at 37° C.
- MIA PaCa-2 cells were seeded at equivalent amounts into either 75 cm 2 flasks, 6-well plates, or 96-well plates (Falcon) and counted 24 hr later to determine plating efficiency.
- Cell number was recorded either by using a mitogenic bioassay, the MTS assay (Cell Titer 96 One Solution, Promega, Madison, Wis.), and measuring absorbency after 4 hr on a Biorad (Model 3550) plate reader at 490 nm, or by counting cells.
- MTS assay Cell Titer 96 One Solution, Promega, Madison, Wis.
- Biorad Model 3550 plate reader
- cells were harvested with a solution of 0.25% trypsin/0.53 mM EDTA, centrifuged, and counted with a hemacytometer. Cell viability was determined by trypan blue staining. At least two aliquots per flask or 4-10 wells/treatment were counted at each time.
- mice Male 4 week old BALB/c-nu/nu nude mice purchased from Harlan Laboratories (Indianapolis, EN) were housed in pathogen-free isolators in the Department of Comparative Medicine at the Penn State University College of Medicine. All procedures were approved by the IACUC committee of the Penn State University College of Medicine and conformed to the guidelines established by NIH. Mice were allowed 48 hr to acclimate prior to beginning experimentation.
- MIA PaCa-2 cells (10 6 cells/mouse) were inoculated into nude mice by subcutaneous injection into the right scapular region; mice were not anesthetized for this procedure.
- mice were weighed weekly throughout the experiment, and observed daily for the presence of tumors. The latency for a visible tumor to appear, and the time until tumors were measurable (i.e., 62.5 mm 3 ) were recorded. Tumors were measured using calipers every day after tumor appearance. Tumor volume was calculated using the formula w 2 ⁇ 1 ⁇ /6, where the length is the longest dimension, and width is the dimension perpendicular to length [31].
- mice were terminated when tumors became ulcerated, or tumors grew to 2 cm in diameter. Forty-five days following tumor cell inoculation, all mice were euthanized by an overdose of sodium pentobarbital (100 mg/kg) and killed by cervical dislocation; mice (with tumors) were weighed. Tumors and spleens were removed and weighed, and the lymph nodes, liver, and spleen examined for metastases.
- trunk blood was collected from some mice in each group.
- Plasma was separated and OGF levels were measured by standard radioimmunoassay procedures using a [Met 5 ]-enkephalin kit from Peninsula Laboratories (Belmont, Calif.).
- Cell numbers and/or absorbencies were analyzed using analysis of variance (ANOVA) (one- or two-factor where appropriate) with subsequent comparisons made using Newman-Keuls tests. Incidence of tumors was analyzed by chi-square tests. Latency for tumor appearance and tumor volume were analyzed using either two-tailed t-tests or ANOVA with subsequent comparisons made using Newman-Keuls tests. Termination data (i.e., body weight, tumor weight, spleen weight) and OGF plasma levels were compared by ANOVA.
- ANOVA analysis of variance
- FIG. 10 Growth curves for MIA PaCa-2 cell cultures treated with 10 ⁇ 6 M OGF (a dosage known to inhibit proliferation of MIA PaCa-2 cells, 44), 10 ⁇ 8 M gemcitabine (a dosage selected because preliminary experiments revealed no logarithmic growth with a dosage of 10 ⁇ 7 M), 10 ⁇ 8 M gemcitabine and 10 ⁇ 6 M OGF, or sterile water (Controls) are presented in FIG. 10 .
- OGF alone inhibited growth at 48, 72, and 96 hr relative to controls, with decreases in cell number of 16%, 18%, and 17%, respectively, noted.
- Gemcitabine alone decreased cell number relative to controls at 48, 72, and 96 hr by 22%, 21%, and 32%, respectively.
- Cells treated with a combination of OGF and gemcitabine were decreased in number relative to controls by 26%, 49%, and 46% at 48, 72, and 96 hr, respectively.
- cell number in cultures receiving the combined therapy of gemcitabine and OGF was reduced (p ⁇ 0.001) from cells exposed only to OGF or gemcitabine by 38% and 36%, respectively.
- the combined therapy of gemcitabine and OGF reduced (p ⁇ 0.001) MIA PaCa-2 cell number by 35% and 20% from cultures receiving only OGF or gemcitabine, respectively.
- MIA PaCa-2 cell cultures were exposed to 5-fluorouracil (5-FU) at a concentration of 10 ⁇ 6 M for 4 days ( FIG. 11 ).
- MIA PaCa-2 cell number in the 5-FU group was reduced 11% to 15% from control levels at 48, 72, and 96 hr.
- Combination therapy of 5-FU (10 ⁇ 6 M) and OGF (10 ⁇ 6 M) reduced cell number from control values at 24, 48, 72, and 96 hr by 13% to 30%.
- the combined therapy of 5-FU and OGF reduced MIA PaCa-2 cell number by 6% to 19% from cultures receiving only OGF, and 10% to 17% from cultures receiving only 5-FU.
- naloxone a short-acting opioid antagonist, naloxone, was added at a dosage of 10 ⁇ 6 M into cultures receiving 10 6 M OGF and/or gemcitabine (10 ⁇ 8 M).
- MIA PaCa-2 cells grown in 96-well plates were treated with 10 ⁇ 6 M OGF, 10 ⁇ 6 M naloxone, 10 ⁇ 8 M gemcitabine, or combinations at the same concentrations—OGF/naloxone, gemcitabine/naloxone, gemcitabine/OGF, and gemcitabine/OGF/naloxone; control cultures received sterile water. Individual plates were read at 96 hr after drug addition.
- the OGF, gemcitabine, gemcitabine-reversal, gemcitabine/OGF, and the gemcitabine/OGF-reversal groups differed from controls by 21% to 46% ( FIGS. 13A , B).
- the OGF-reversal group had 16% more cells than in the OGF group continuing with OGF exposure.
- the gemcitabine-reversal group did not differ from cell cultures continuing to be treated with gemcitabine.
- Cell cultures exposed to the combination of OGF and gemcitabine had 7% fewer cells than cultures in the gemcitabine/OGF-reversal group.
- MIA PaCa-2 cultures 1,000 cells/well were treated daily with 10 ⁇ 6 M concentrations of a variety of natural and synthetic opioid ligands. In some cases, these ligands were specific for other opioid receptors (e.g., ⁇ , ⁇ , or ⁇ receptors).
- Drugs included OGF, DAMGO, morphine, DPDPE, DADLE, dynorphin A1-8, endomorphin-1, endomorphin-2, and ⁇ -endorphin. Cell number was measured on a plate reader after 96 hr of treatment (both drug and media were changed daily). OGF inhibited cell number by 16% relative to controls; none of the other drugs utilized had any inhibitory or stimulatory effect on growth ( FIG. 14 ).
- nude mice were injected with MIA PaCa-2 cells and treated with drugs.
- On day 10 when 80% of the mice in the saline-injected control group had measurable tumors, and 60% of the OGF and 75% of the gemcitabine-treated animals had tumors, no mouse in the gemcitabine/OGF group had a measurable tumor; the group receiving combination therapy of gemcitabine and OGF differed significantly from all other groups at p ⁇ 0.001 (Table 6).
- no differences in the incidence of measurable tumors could be detected between groups, and all animals had a tumor by day 17.
- the latency time for the appearance of a visible tumor in mice of the gemcitabine/OGF group was delayed by approximately 5 to 6 days from animals in the control, OGF, and gemcitabine groups; this delay for the gemcitabine/OGF group differed significantly from that of all other groups at p ⁇ 0.05.
- the mean latency tine for measurable tumor appearance in mice of the gemcitabine/OGF group was delayed (p ⁇ 0.05) by approximately 6 days from animals in the control, OGF, and gemcitabine groups.
- OGF levels in the plasma of nude mice bearing MIA PaCa-2 tumors ranged from 129 to 289 pg/ml. No differences were noted between control mice and those treated with OGF alone, gemcitabine alone, or gemcitabine/OGF.
- This naloxone-sensitive receptor is presumed to be OGFr, because synthetic and natural opioids selective for classical opioid receptors such as ⁇ , ⁇ , and ⁇ did not influence growth of pancreatic cancer cells in the present report and earlier [44].
- OGF also was discovered to have a reversible action on the replication of MIA PaCa-2 cells, supporting the result from earlier studies showing that treatment with this compound does not lead to cytotoxicity or cell death [39, 44].
- the effects of gemcitabine on MIA PaCa-2 cells were neither blocked by naloxone nor could they be reversed, indicating that the characteristics of this drug's effects on MIA PaCa-2 cells is markedly different from that of OGF.
- this is the first report of the efficacy of using a combination of the biotherapeutic agent, OGF, and the chemotherapeutic agent, gemcitabine, to retard the growth of human pancreatic cancer.
- the present results are the first to show that the effects of a combination of 5-FU and OGF has potent inhibitory properties with respect to human pancreatic cancer.
- the effect of a combination of 5-FU and OGF on pancreatic cancer cells was markedly greater than that of each drug and was often additive in nature. Presumably, these results would indicate that OGF could be used in combination with a variety of chemotherapeutic agents.
- OGF is targeted to the G 0 /G 1 phase of the cell cycle and produces a notable delay in pancreatic cancer cell growth [41], but does not induce apoptosis [39].
- Gemcitabine and 5-FU are cytotoxic and induce programmed cell death [9, 27, 30]. Therefore, the cytostatic action of OGF could be envisioned to channel cells into the apoptotic pathway associated with gemcitabine or 5-FU.
- Gemcitabine is the standard of care for metastatic cancer [7, 13, 17, 24, 42], and is in clinical trials as a single-agent chemotherapeutic for locally advanced pancreatic cancer [1]. Treatment with gemcitabine is not curative for metastatic disease, and treatment with this agent as to its palliative benefit must be examined in the face of such factors as toxicity [1, 17]. Given the urgent need for advancement in the treatment of pancreatic cancer, combinations of drug therapies, many of which involve a new agent plus gemcitabine, for pancreatic cancer have gained attention [5, 7, 17, 24]. The present report raises the exciting potential of combining chemotherapy and biotherapy into a novel treatment modality for human pancreatic cancer.
- OGF is not toxic, avoids problems related to drug resistance, has easy accessibility, and can be integrated into the chronic use of chemotherapeutic agents. Moreover, it introduces the possibility of using chemotherapeutic agents at less toxic concentrations and/or in chronic regimens (metronomic chemotherapy) [see 10, 16] in combination with a biotherapy. OGF used as a single-agent has been successful in a Phase I clinical trial with patients with advanced unresectable pancreatic adenocarcinoma [33]. During the chronic experiments in this study by Smith and colleagues [33], mean survival from the time of diagnosis was 8.7 to 9.5 months, depending on the route of drug administration, with some patients living as long as 23 months.
- This study evaluated the effects of a combination of Opioid Growth Factor (OGF) and paclitaxel on squamous cell carcinoma of the head and neck (SCCHN) using a tissue culture model of human SCCHN.
- OGF Opioid Growth Factor
- SCCHN head and neck
- the combination of OGF and paclitaxel was markedly inhibitory to SCCHN proliferation, reducing growth from control levels by 48% to 69% within 48 hr.
- OGF in combination with carboplatin also depressed cell growth.
- the effect of a combination of OGF and paclitaxel or carboplatin on SCCHN growth was supra-additive, being greater than either of the individual compounds.
- the action of OGF, but not paclitaxel, was mediated by a naloxone-sensitive receptor and was completely reversible.
- OGF but no other endogenous or exogenous opioid, altered replication of SCCHN.
- OGF and paclitaxel depressed DNA synthesis, whereas only paclitaxel induced apoptosis.
- the combination of OGF and paclitaxel also had a supra-additive effect on the growth of another SCCHN, CAL-27, indicating the ubiquity of the combined drug activity.
- the UM-SCC-1 cell line (SCC-1) was derived from a well-differentiated recurrent squamous cell carcinoma in the floor of the mouth of a 73-yr old male (25). This cell line was obtained from The University of Michigan, Cancer Research Laboratory (Thomas E. Carey, Ph.D., Director). CAL-27 human squamous cell carcinoma cell line, derived from a poorly differentiated carcinoma of the tongue in a 56-yr old male (26), was obtained from the American Type Culture Collection (Manassas, Va.).
- Both cell lines were grown in Dulbecco's MEM (modified) media supplemented with 10% fetal calf serum, 1.2% sodium bicarbonate, and antibiotics (5,000 Units/ml penicillin, 5 mg/ml streptomycin, 10 mg/ml neomycin).
- the cell cultures were maintained in a humidified atmosphere of 7% CO 2 /93% air at 37° C.
- OGF 10 ⁇ 6 M
- paclitaxel 10 ⁇ 8 M
- OGF was prepared in sterile water and paclitaxel was dissolved in DMSO at a concentration of 10 ⁇ 2 M and further diluted into sterile water; dilutions represent final concentrations of the compounds.
- the concentration of OGF that was utilized was selected based on previous evidence demonstrating growth inhibition of SCCHN (13); the concentration of paclitaxel was selected from preliminary studies in our laboratory demonstrating that paclitaxel at 10 ⁇ 8 M, but not 10 ⁇ 7 M, inhibited cell growth but did not eliminate all cells over a 5-6 day period of time (15).
- MTS proliferation bioassay Cell Titer 96 One Solution, Promega, Madison, Wis.
- Biorad Model 3550 plate reader
- the MTS assay utilized 10 wells/treatment.
- cells were harvested by trypsinization with 0.25% trypsin/0.53 mM EDTA, centrifuged, and counted with a hemacytometer.
- Cell viability was determined by trypan blue staining. At least two aliquots per well, and 4-10 wells/treatment, were counted at each time for manual counting.
- the rate of growth over a 96-hr period of time was calculated using linear regression analyses.
- the slopes of the lines were compared by analysis of variance. All calculations were performed with GraphPad Prism software.
- paclitaxel and/or OGF the effects of these drugs on DNA synthesis (BrdU incorporation), apoptosis (caspase-3 activity), and necrosis (trypan blue positivity) were evaluated.
- SCC-1 cells were seeded onto 22 mm diameter coverglasses placed in 6-well plates (3 ⁇ 10 3 cells/coverglass). Cells were treated with paclitaxel (10 ⁇ 8 M) and/or OGF (10 ⁇ 6 M) for 24 or 72 hr; media and drugs were replaced daily. Three hours prior to fixing cells, 30 ⁇ M BrdU was added to cultures.
- cells were rinsed, fixed in 10% neutral buffered formalin, and stained with antibodies to BrdU (Roche, Indianapolis, Ind.). The number of positive cells was recorded using fluorescence microscopy. At least 1000 cells/treatment at each time were counted.
- Caspase-3-FITC positive staining was used to characterize early stages of apoptosis (29).
- SCC-1 cells were seeded into 6-well plates and treated with drugs beginning 24 hr later; drugs and media were replaced daily. Cells were harvested after 1, 3 and 6 days of drug treatment, and prepared according to manufacturer's recommendations for FACS analysis (FACS cell sorter with a 15 mW argon ion laser at 488 nm; Becton, Dickinson and Company, Franklin Lakes, N.J.).
- FACS cell sorter with a 15 mW argon ion laser at 488 nm; Becton, Dickinson and Company, Franklin Lakes, N.J.
- the APO-ACTIVE 3 antibody detection kit was used for caspase-3 identification. Three samples from each treatment were analyzed at each time point. The percent gated cells recorded by flow cytometry was considered caspase positive.
- Exposure of SCC-1 cells to both OGF and carboplatin reduced cell number from the OGF group by approximately 7-20% at 48-96 hr, and from the group treated with carboplatin alone by approximately 14% and 12% at 48 and 72 hr, respectively.
- naloxone 10 ⁇ 6 M
- OGF vascular endothelial growth factor
- naloxone 10 ⁇ 6 M
- paclitaxel/naloxone paclitaxel/OGF
- paclitaxel/OGF paclitaxel/OGF/naloxone
- the OGF-reversal group had 16% more cells than the OGF group continuing with OGF exposure, however the paclitaxel-reversal group did not differ from cells continuing to be treated with paclitaxel ( FIGS. 20A , B).
- Cell cultures exposed to the combination of OGF and paclitaxel had significantly fewer cells than cultures treated with OGF or paclitaxel alone, as well as the combination of these drugs withdrawn after 48 hr.
- the paclitaxel/OGF-reversal group did not differ from the paclitaxel alone or paclitaxel-reversal groups.
- Opioid Peptide(s) Related to Head and Neck Cancer Cell Growth.
- SCC-1 cultures 1000 cells/well were treated daily with 10 ⁇ 6 M concentrations of a variety of natural and synthetic opioid ligands ( FIG. 21 ); in some cases, these ligands were specific for ⁇ , ⁇ , or ⁇ opioid receptors.
- Drugs included OGF, morphine, DAMGO, DPDPE (d-Pen,d-Pen-enkephalin), DADLE (d-Ala-D-Leu-enkephalin), dynorphin 1-13, endomorphin-1, endomorphin-2, and ⁇ -endorphin. Except for OGF, which had a 19% decrease from control levels in absorbency readings, none of the drugs utilized had any inhibitory or stimulatory effect on growth.
- BrdU labeling of SCCHN cells for 3 hours and treatment for 24 hours with OGF, paclitaxel, or OGF and paclitaxel showed a 31%, 24%, and 33%, respectively, decrease in the number of positive cells relative to controls ( FIG. 23 ).
- the number of BrdU positive cells was decreased 61% from control levels in the OGF-treated cultures.
- the number of BrdU labeled cells was reduced 24% and 16% from control levels in the paclitaxel or paclitaxel-OGF treated cultures, respectively.
- a dosage of 10 ⁇ 10 M paclitaxel was chosen for further study in order to examine the magnitude of the combination of OGF and paclitaxel in the face of a lower level of toxicity.
- exposure of CAL-27 cells to either OGF (10 ⁇ 6 M), paclitaxel (10 ⁇ 10 M), or OGF (10 ⁇ 6 M) and paclitaxel (10 ⁇ 10 M) revealed 25%, 35%, and 61%, respectively, fewer cells than in control cultures.
- This naloxone-sensitive receptor is presumed to be OGFr, because synthetic and natural opioids selective for classical opioid receptors such as ⁇ , ⁇ , and ⁇ did not influence cell replication of SCC-1 as demonstrated in the present report and earlier (13, 22). OGF also was found to have a reversible action on the replication of SCC-1, supporting the results from earlier studies showing that treatment with this compound does not lead to cytotoxicity and cell death (13, 21). On the other hand, the effects of paclitaxel on SCC-1 cells were neither blocked by naloxone nor could be reversed, indicating that the characteristics of this drug's action on SCC-1 is markedly different from that of OGF. Thus, this is the first report of the efficacy of using a combination of the biotherapeutic agent, OGF, and the chemotherapeutic agent, paclitaxel, to retard the growth of SCCHN.
- Paclitaxel is a chemotherapeutic agent that prevents microtubule depolymerization resulting in the arrest of proliferating cells in the G 2 -M phase of the cell cycle and leading to cell death (33, 34). Additionally, paclitaxel modulates a number of intracellular events which result in cellular apoptosis and ensuing nuclear degradation (35). OGF is known to not influence apoptosis (21), but is targeted to the G 0 /G 1 phase of the cell cycle (17). Our experiments showed that SCCHN exposed to paclitaxel resulted in a marked increase in the number of apoptotic cells within 3 days of initiation of drug treatment.
- OGF and carboplatin had an additive effect on growth.
- these results indicate that OGF could be used in combination with more than one family of chemotherapeutic agents (i.e., taxanes, platinums) to enhance antitumor activity.
- chemotherapeutic agents i.e., taxanes, platinums
- Further studies are needed to characterize the mode of action of a combination of these two drugs. The end result may be that OGF is a cytostatic drug, whereas paclitaxel and carboplatin induce programmed cell death, and that OGF contributes to cell death by channeling cells into the apoptotic pathway.
- Paclitaxel has been reported to be active in the treatment of squamous cell carcinoma of the head and neck, and Phase II evaluation has been successful (6). Used as a single-agent therapy for SCCHN, this drug improved response rate, as well as median survival time, in comparison to cisplatin and 5-fluorouracil combination chemotherapy. However, 91% of the patients exposed to paclitaxel experienced neutropenia. Although OGF has been approved in Phase I trials (41), OGF has not been used clinically for the treatment of SCCHN. However, the efficacy of this compound has been demonstrated in xenograft experiments (14, 16). The present report raises the exciting potential of combining chemotherapy and biotherapy into a novel treatment modality for SCCHN.
- the present report addresses the question of whether a combination of OGF and paclitaxel influences growth of human SCCHN in vivo, and does so beyond the efficacy of each compound.
- the UM-SCC-1 cell line (SCC-1) [8] was obtained from Cancer Research Laboratory at The University of Michigan (Dr. Thomas E. Carey, Director). Cells were grown in Dulbecco's MEM (modified) media supplemented with 10% fetal calf serum, 1.2% sodium bicarbonate, and antibiotics (5,000 Units/ml penicillin, 5 mg/ml streptomycin, 10 mg/ml neomycin). The cell cultures were maintained in a humidified atmosphere of 7% CO 2 /93% air at 37° C. Cells were harvested by trypsinization with 0.05% trypsin/0.53 mM EDTA, centrifuged, and counted with a hemacytometer. Cell viability was determined by trypan blue staining.
- mice Male 4 week old nu/nu nude mice purchased from Harlan Laboratories (Indianapolis, Ind.) were housed in pathogen-free isolators in the Department of Comparative Medicine at the Penn State University College of Medicine. All procedures were approved by the IACUC committee of the Penn State University College of Medicine and conformed to the guidelines established by NIH. Mice were allowed 48 hr to acclimate prior to beginning experimentation.
- Tumor cells were inoculated into nude mice by subcutaneous injection into the right scapular region. Subcutaneous injections were performed with at least 2 ⁇ 10 6 cells per mouse; mice were not anesthetized for this procedure.
- OGF was injected prior to paclitaxel. Dosages were selected based on published reports [1, 17]. Paclitaxel was dissolved in DMSO and then diluted in sterile saline; OGF was dissolved in sterile saline. Injections of drugs were initiated 1 hr after tumor cell inoculation.
- mice were observed daily for the presence of tumors. The latency for a visible tumor to appear, and the time until tumors were measurable (i.e., 62.5 mm 3 ), were recorded. Tumors were measured using calipers every day. Tumor volume was calculated using the formula w 2 ⁇ 1 ⁇ /6, where the length is the longest dimension, and width is the dimension perpendicular to length [24].
- mice were terminated when tumors became ulcerated, or tumors grew to 2 cm in diameter. Fifty 50 days following tumor cell inoculation and approximately 35-40 days following initial tumor appearance, all mice were euthanized by an overdose of sodium pentobarbital (100 mg/kg) and killed by cervical dislocation; mice (with tumors) were weighed. Tumors and spleens were removed and weighed, and the lymph nodes, liver, and spleen examined for metastases.
- sodium pentobarbital 100 mg/kg
- cervical dislocation mice
- Tumor tissues from some mice in each treatment group were removed at the time of death, washed free of blood and connective tissue, and immediately frozen in liquid nitrogen. Tissues were assayed following the procedures published previously [16]. Saturation binding isotherms were generated using GraphPad Prism software; binding affinity (K d ) and capacity (B max ) values were provided by the computer software.
- trunk blood was collected from several mice in each group.
- Plasma was separated and OGF levels were measured by standard radioimmunoassay procedures using a kit from Peninsula Laboratories (Belmont, Calif.). Plasma samples were assayed in duplicate.
- Incidence of tumors was analyzed by chi-square tests. Latency for tumor appearance and tumor volume were analyzed using analysis of variance (ANOVA) with subsequent comparisons made using Newman-Keuls tests. Growth of tumors, termination day data (i.e., body weight, tumor weight, spleen weight), plasma levels of OGF, as well as binding capacity and affinity of tumors, were compared by ANOVA and Newman-Keuls tests.
- ANOVA analysis of variance
- mice in the saline-injected control group had measurable tumors
- these values differed significantly at p ⁇ 0.05 (Table 8).
- fewer mice in the paclitaxel and paclitaxel/OGF groups (66% and 70%, respectively) had measurable tumors compared to controls, these differences were not statistically significant.
- 100% of the control mice had measurable tumors
- only 66% of the mice receiving OGF had tumors
- 83% and 90% of the animals in the paclitaxel and paclitaxel/OGF groups had tumors; however, no significant differences were recorded (Table 9).
- mice inoculated with SCC-1 cells developed tumors (Table 8), with 100% of the mice in the control group having tumors by day 17 and every animal in the other groups having a measurable tumor by day 28.
- the latency time for mice receiving OGF to develop visible tumors was 11 days in comparison to controls that had a mean latency of 7 days; this four-day delay was significantly different at p ⁇ 0.02 (Table 8).
- the mean latency time for visible tumors to appear was comparable between mice in the control group and in the paclitaxel and paclitaxel/OGF groups.
- the mean latency time until tumors became measurable ranged from 14 to 17 days, and did not differ between groups.
- the weights of tumors on termination day (day 50) in the OGF and the paclitaxel/OGF groups were reduced 29% and 62%, respectively, from control levels (Table 9).
- Evaluation of tumor volume on day 50 revealed the OGF and paclitaxel/OGF groups had a reduction of 33% and 69%, respectively, from control values (Table 9). Because only one mouse in the paclitaxel group was alive at this timepoint, analysis of tumor weight or volume were performed. Measurements of tumor weight and volume in the paclitaxel/OGF group on day 50 also revealed a decrease of 47% and 53%, respectively, from that occurring in the OGF group.
- mice receiving paclitaxel had a 10% reduction in body weight at week 5 of the study and were subnormal by 9-10% on weeks 6 and 7.
- mice receiving paclitaxel weighed 28% less than control subjects, and were significantly less (p ⁇ 0.001) in body weight than mice in the OGF and paclitaxel/OGF groups (Table 9). No differences in body weights between control animals and those in the OGF or paclitaxel/OGF groups were recorded.
- Spleen weights did not differ among groups. In addition, no metastases were noted in the spleens, liver, or axillary lymph nodes of mice in any group.
- OGF levels in the plasma of nude mice bearing SCC-1 tumors ranged from 282 to 617 pg/ml. No differences were noted between control mice with tumors and those treated with OGF, paclitaxel, or paclitaxel/OGF.
- the present results show that a combination of OGF and paclitaxel has a potent inhibitory effect on the growth of SCC-1 in nude mice, a well-differentiated human tumor model of SCCHN.
- the antigrowth action of OGF and paclitaxel was synergistic, with the total inhibitory activity being greater than the sum of the parts (i.e., OGF or paclitaxel alone).
- This supra-additive effect of OGF and paclitaxel was most evident in measurements of tumor weight and volume.
- Paclitaxel is a chemotherapeutic agent that prevents microtubule depolymerization resulting in the arrest of proliferating cells in the G 2 -M phase of the cell cycle which leads to cell death [31, 32]. Additionally, paclitaxel modulates a number of intracellular events which result in cellular apoptosis and ensuing nuclear degradation [27]. OGF does not influence apoptosis [31], but is targeted to the G 0 /G 1 phase of the cell cycle [32]. Earlier experiments in tissue culture showed that SCCHN exposed to paclitaxel resulted in a marked increase in the number of apoptotic cells.
- the mechanism for the enhanced growth inhibition in vivo by the combined effect of OGF and paclitaxel could be related to delays in the cell cycle (the effect of OGF) which results in the recruitment of cells into the apoptotic pathway (the effect of paclitaxel).
- Paclitaxel has been reported to be active in the treatment of squamous cell carcinoma of the head and neck, and Phase II evaluation has been successful [4]. Used as a single-agent therapy for SCCHN, this drug improved response rate, as well as median survival time, in comparison to cisplatin and 5-fluorouracil combination chemotherapy. However, 91% of the patients exposed to paclitaxel experienced neutropenia. Although OGF has been approved in Phase I trials [26], OGF has not been used clinically for the treatment of SCCHN. However, the efficacy of this compound for treatment of SCCHN has been demonstrated in xenograft experiments [16, 17]. The present report raises the exciting potential of combining chemotherapy and biotherapy into a novel treatment modality for SCCHN. With the preclinical information that a combination of OGF and paclitaxel has a synergistic effect on SCCHN in xenografts, the prospect of clinical studies should be considered.
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US13/020,077 Abandoned US20110123437A1 (en) | 2004-02-26 | 2011-02-03 | Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor |
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US15/159,334 Abandoned US20160256517A1 (en) | 2004-02-26 | 2016-05-19 | Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor |
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US13/020,077 Abandoned US20110123437A1 (en) | 2004-02-26 | 2011-02-03 | Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor |
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EP (1) | EP1732583A4 (fr) |
JP (1) | JP2007525507A (fr) |
AU (1) | AU2005216898A1 (fr) |
CA (1) | CA2557504C (fr) |
WO (1) | WO2005082397A1 (fr) |
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EP1732583A4 (fr) | 2004-02-26 | 2009-08-12 | Penn State Res Found | Therapie combinatoires pour le traitement des neoplasies a l'aide des recepteurs du facteur de croissance opioide |
US20070142287A1 (en) * | 2005-12-20 | 2007-06-21 | Biomed Solutions, Llc | Compositions And Methods For Treatment Of Cancer |
WO2009046826A1 (fr) * | 2007-09-11 | 2009-04-16 | Mondobiotech Laboratories Ag | Utilisation d'un pentapeptide cyclique en tant qu'agent thérapeutique |
RU2010114024A (ru) * | 2007-09-11 | 2011-10-20 | Мондобайотек Лабораториз Аг (Li) | Применение гонадорелина в качестве терапевтического средства |
JP4593639B2 (ja) * | 2008-03-04 | 2010-12-08 | 株式会社マルハニチロ食品 | ペプチド含有摂食調節剤 |
US8758323B2 (en) | 2009-07-30 | 2014-06-24 | Tandem Diabetes Care, Inc. | Infusion pump system with disposable cartridge having pressure venting and pressure feedback |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
EP2716291B1 (fr) * | 2012-10-08 | 2019-11-27 | Universität Ulm | Combinaison d'opioïdes et médicaments anticancéreux pour le traitement du cancer |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
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US4537878A (en) * | 1981-10-05 | 1985-08-27 | Tni Pharmaceuticals, Inc. | Process for using endogenous enkephalins and endorphins to stimulate the immune system |
US4757049A (en) * | 1981-10-05 | 1988-07-12 | Tni Pharmaceuticals, Inc. | Process for using endogenous enkephalins and endorphins to stimulate the immune system of patients with aids |
US6136780A (en) | 1996-03-29 | 2000-10-24 | The Penn State Research Foundation | Control of cancer growth through the interaction of [Met5 ]-enkephalin and the zeta (ζ) receptor |
US7037889B2 (en) * | 2000-09-13 | 2006-05-02 | Praecis Pharmaceuticals Inc. | Pharmaceutical compositions for sustained drug delivery |
US20070053838A1 (en) | 2004-02-26 | 2007-03-08 | Zagon Ian S | Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor |
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US4892874A (en) * | 1986-11-04 | 1990-01-09 | Southern Research Institute | Synergistic anticancer combination |
TWI283575B (en) * | 2000-10-31 | 2007-07-11 | Eisai Co Ltd | Medicinal compositions for concomitant use as anticancer agent |
SI1385551T1 (sl) * | 2001-04-06 | 2008-12-31 | Wyeth Five Giralda Farms | Antineoplastiäśne kombinacije, ki vsebujejo cci-779 (derivat rapamicina) skupaj z gemcitabinom ali fluorouracilom |
AU2002352941A1 (en) * | 2001-11-30 | 2003-06-17 | Schering Corporation | Use of an farsenyl protein tranferase inhibitor in combination with other antineoplastic agents for the manufacture of a medicament against cancer |
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2005
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- 2005-02-21 CA CA2557504A patent/CA2557504C/fr active Active
- 2005-02-21 JP JP2007500893A patent/JP2007525507A/ja active Pending
- 2005-02-21 AU AU2005216898A patent/AU2005216898A1/en not_active Abandoned
- 2005-02-21 US US11/061,932 patent/US10668126B2/en not_active Expired - Fee Related
- 2005-02-21 WO PCT/US2005/005268 patent/WO2005082397A1/fr active Application Filing
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2011
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2020
- 2020-05-05 US US16/867,336 patent/US20210046147A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4537878A (en) * | 1981-10-05 | 1985-08-27 | Tni Pharmaceuticals, Inc. | Process for using endogenous enkephalins and endorphins to stimulate the immune system |
US4757049A (en) * | 1981-10-05 | 1988-07-12 | Tni Pharmaceuticals, Inc. | Process for using endogenous enkephalins and endorphins to stimulate the immune system of patients with aids |
US6136780A (en) | 1996-03-29 | 2000-10-24 | The Penn State Research Foundation | Control of cancer growth through the interaction of [Met5 ]-enkephalin and the zeta (ζ) receptor |
US7037889B2 (en) * | 2000-09-13 | 2006-05-02 | Praecis Pharmaceuticals Inc. | Pharmaceutical compositions for sustained drug delivery |
US20070053838A1 (en) | 2004-02-26 | 2007-03-08 | Zagon Ian S | Combinatorial therapies for the treatment of neoplasias using the opioid growth factor receptor |
Non-Patent Citations (36)
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US20110123437A1 (en) | 2011-05-26 |
EP1732583A1 (fr) | 2006-12-20 |
AU2005216898A1 (en) | 2005-09-09 |
US20160256517A1 (en) | 2016-09-08 |
US20070053838A1 (en) | 2007-03-08 |
WO2005082397B1 (fr) | 2005-11-10 |
US20210046147A1 (en) | 2021-02-18 |
CA2557504A1 (fr) | 2005-09-09 |
US20050191241A1 (en) | 2005-09-01 |
JP2007525507A (ja) | 2007-09-06 |
US8003630B2 (en) | 2011-08-23 |
US20130084242A1 (en) | 2013-04-04 |
US9375458B2 (en) | 2016-06-28 |
WO2005082397A1 (fr) | 2005-09-09 |
EP1732583A4 (fr) | 2009-08-12 |
CA2557504C (fr) | 2020-12-01 |
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